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Imidazolidinedione compounds and their uses

Active Publication Date: 2014-12-18
HINOVA PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention has the following benefits:

Problems solved by technology

However, with the social development and progress in our country, the aging of society, urbanization, westernization of dietary structure and advances in detection technology, the incidence of prostate cancer was significantly increased.
However, patients will develop drug resistance after 2-4 years treatment, while bicalutamide has side effects of stimulating the proliferation of cancer, therefore patients must stop using bicalutamide.

Method used

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  • Imidazolidinedione compounds and their uses
  • Imidazolidinedione compounds and their uses
  • Imidazolidinedione compounds and their uses

Examples

Experimental program
Comparison scheme
Effect test

example 1

4-[7-(4-cyano-2-trifluoromethyl-phenyl)-8-oxo-6-thio-5,7-diazaspiro[3,4]-5-octyl]-2-fluoro-N-methyl benzamide (compound 7, as control compound 1)

[0086]

Synthesis of 4-isothiocyanato-2-(trifluoromethyl)-benzyl cyanide (compound 2)

[0087]Into an aqueous suspension (50 mL) of thiophosgene (30.2 g, 262.4 mmol) compound 1 (10.0 g, 53.7 mmol) was slowly added in portions. The reaction mixture was stirred at room temperature (20° C.) for one hour and then extracted with ethyl acetate for three times (3×50 mL). The organic layer was combined, washed with saturated brine (100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to give a black solid. After purified by column chromatography, a white solid (Compound 2, 11.24 g, yield 92%) was obtained. 1H NMR (CDCl3, 400 MHz): δ(ppm) 7.85 (1H, d, J=8 Hz), 7.59 (1H, s), 7.48 (1H, d, J=8.4 Hz). MS: 229 (M+H+).

Synthesis of 2-fluoro-N-methyl-4-nitro-benzamide (Compound 4)

[0088]

[0089]Into a dichloromethane solution (200 mL) of compou...

example 2

4-[7-(4-cyano-2-trifluoromethyl-phenyl)-8-oxo-6-thio-5,7-diazaspiro[3,4]-5-octyl]-2-fluoro-N,N-dimethyl benzamide (Compound 11)

[0096]

Synthesis of 2-fluoro-N,N-dimethyl-4-nitro-benzamide (Compound 8)

[0097]

[0098]Into a solution of compound 3 (25 g, 135.06 mol) in methylene chloride (200 mL)

[0099]CDI (32.8 g, 202.28 mmol) was added. The reaction mixture was stirred at room temperature for one hour. Into a solution of dimethylamine hydrochloride (13.22 g, 162.12 mmol) in dichloromethane (50 mL) triethylamine (20.47 g, 202.29 mmol) was added to give a white suspension. After stirred at room temperature for half an hour, the suspension was added to the reaction mixture slowly. After the resulting mixture was stirred for one hour, the reaction was quenched by adding water (100 mL). The organic phase was separated and the aqueous phase was extracted with dichloromethane twice (2×50 mL). The organic phases were combined, washed with 1 M hydrochloric acid twice (2×50 mL), 1 M aqueous sodium h...

example 3

4-[7-(4-cyano-2-trifluoromethyl-phenyl)-8-oxo-6-thio-5,7-diazaspiro[3,4]-5-octyl]-2-fluoro-N-trideuteromethyl-benzamide (compound 15)

[0106]

Synthesis of 2-fluoro-N-trideuteromethyl-4-nitro-benzamide (compound 12)

[0107]

[0108]Into a solution of compound 3 (5.25 g, 28.37 mol) in dichloromethane (20 mL) CDI (4.62 g, 28.37 mmol) was added. The reaction mixture was stirred at room temperature for one hour. Into a solution of trideuterated methylamine hydrochloride (2 g, 28.76 mmol) in methylene chloride (20 mL) triethylamine (3.27 g, 32.36 mmol) was added to give a white suspension. After stirred at room temperature for half an hour, the suspension was added to the reaction mixture slowly. The resulting mixture was stirred for another hour, the reaction was quenched by adding water (10 mL). The organic phase was separated and the aqueous phase was extracted with dichloromethane (2×20 mL) twice. The organic phases were combined, washed with 1 M hydrochloric acid (2×10 mL) twice, 1 M aqueous...

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Abstract

Provided are imidazolidinedione compounds of formula (I), processes for preparation, uses and pharmaceutically compositions thereof. Said imidazolidinedione compounds posses androgen receptor antagonist activity and can be used for preventing and treating diseases and disorders related to androgen receptor, such as prostate cancer, alopecia, hair regeneration, acne and adolescent acne.

Description

TECHNICAL FIELD[0001]The invention relates to the field of medicine, in particular, to imidazolidinedione compounds and uses thereof. More specifically, the invention relates to imidazolidinedione compounds and its use as androgen receptor antagonists or for the treatment and prevention of diseases related to androgen receptor.BACKGROUND[0002]Prostatic cancer (prostatic carcinoma, abbreviated as PCa) is the most common malignant neoplasmin in male reproductive system. The incidence thereof increases with age, and differs significantly from region to region, which is higher in U.S. and Europe. Second to lung cancer, prostatic cancer is the second cancer leading to death in men. In the past, prostatic cancer has not been paid attention in China, since it belongs to a small disease in the spectrum of tumor. However, with the social development and progress in our country, the aging of society, urbanization, westernization of dietary structure and advances in detection technology, the i...

Claims

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Application Information

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IPC IPC(8): C07D235/02C07D233/86
CPCC07D233/86C07D235/02C07D233/72A61K31/4166A61K31/4184A61P5/28A61P13/08A61P17/00A61P17/02A61P17/08A61P17/10A61P17/14A61P35/00A61P43/00
Inventor CHEN, YUANWEI
Owner HINOVA PHARM INC
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